1. Field of the Invention
This invention relates to cosolvent formulations for therapeutic agents, the formulations having a synergistic preservative effect.
2. Discussion of the Prior Art
There is a continuing need to develop efficacious formulations for therapeutic agents that offer advantages in manufacturing, processing and safety for the patient. In particular, many therapeutic agents, for example vitamin D compounds, are oxygen sensitive or are otherwise unstable. Thus, the need to protect such compounds has lead to the routine addition of antioxidants in order to preserve the integrity of the active agent. In other formulations, buffers may be necessary to maintain pH. Chelating agents, including but not limited to citric acid, tartaric acid, amino acids, thioglycolic acid, and edetate disodium (EDTA), and buffers, including but not limited to acetate, citrate, glutamate, and phosphate buffers, are often used to stabilize formulations. However, as discussed in WO 96/36340, buffers and chelating agents have been implicated in imparting aluminum levels in products to in excess of 3.5 parts per million at the expiration date of the product.
It would be particularly advantageous to minimize aluminum levels in formulations for parenteral administration for patients on dialysis to minimize the risk of aluminum accumulation as these patients may develop osteomalacia. Potential adverse effects of EDTA may also include nephrotoxicity and renal tubular necrosis. Furthermore, EDTA is a chelating agent that is not an approved excipient in some international markets, such as Japan.
The present invention provides a formulation that overcomes these and other problems associated with pharmaceutical formulations. The present invention provides a formulation that requires no antioxidant, contains no additives that would lead to an increase in the levels of aluminum in the formulation, and may be terminally sterilized. It has also been surprisingly discovered that the novel formulations of the invention provide a synergistic preservative effect that could not be predicted from the anti-microbial effect of the alcohol and gylcol derivative as individual agents.
The present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a therapeutic agent and an organic solvent selected from low molecular weight alcohols and glycol derivatives. The formulations of the invention provide a synergistic preservative effect. The term xe2x80x9csynergistic preservative effectxe2x80x9d means a preservative effect that is not additive, as would be predicted from the individual effect of each agent, but is instead gives a level of preservation which is above that which would be predicted, i.e., is synergistic. The preservative effect is measured following the guidelines of USP 23.
Preferred embodiments provide compositions comprising vitamin D compounds, ethanol and propylene glycol (PG). More preferred are compositions comprising paracalcin, ethanol, propylene glycol and further comprising water. Most preferred are compositions comprising paracalcin, 20% (v/v) ethanol, 30% (v/v) PG, and 50% (v/v) water.
A further embodiment of the invention provides a solution that is suitable to provide a synergistic preservative effect to therapeutic agents dissolved therein.
A further embodiment of the invention provides terminally sterilized formulations of the present invention.
Yet another embodiment of the present invention is a formulation which provides a final dosage form of paracalcin which contains 5 xcexcg/ml paracalcin, ethanol, propylene glycol, and water.
Processes for preparing such sterile, cosolvent solutions are also disclosed.